Abstract
Purpose
Reactive oxygen species (ROS) are produced in cancer cells as a result of increased metabolic rate, dysfunction of mitochondria, elevated cell signaling, expression of oncogenes and increased peroxisome activities. Certain level of ROS is required by cancer cells, above or below which lead to cytotoxicity in cancer cells. This biochemical aspect can be exploited to develop novel therapeutic agents to preferentially and selectively target cancer cells.
Methods
We searched various electronic databases including PubMed, Web of Science, and Google Scholar for peer-reviewed english-language articles. Selected articles ranging from research papers, clinical studies, and review articles on the ROS production in living systems, its role in cancer development and cancer treatment, and the role of microbiota in ROS-dependent cancer therapy were analyzed.
Results
This review highlights oxidative stress in tumors, underlying mechanisms of different relationships of ROS and cancer cells, different ROS-mediated therapeutic strategies and the emerging role of microbiota in cancer therapy.
Conclusion
Cancer cells exhibit increased ROS stress and disturbed redox homeostasis which lead to ROS adaptations. ROS-dependent anticancer therapies including ROS scavenging anticancer therapy and ROS boosting anticancer therapy have shown promising results in vitro as well as in vivo. In addition, response to cancer therapy is modulated by the human microbiota which plays a critical role in systemic body functions.
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Introduction
It is impossible to imagine life without oxygen, but its consumption has some consequences that threaten the balance of life. Cellular respiration can give rise to molecules called reactive oxygen species or ROS. ROS are oxygen byproducts that contain single or more unpaired electrons in their outermost shell and are generated from molecular oxygen. Molecular oxygen contain two unpaired electrons in the outermost shell are at ground state. Due to similar spinning of these electrons, oxygen is not in a very reactive state. Conversely, oxygen becomes highly reactive when one of these two unpaired electrons becomes excited as two electrons with different spins can immediately react with other electrons, particularly with double bonds. When oxygen is reduced by one electron at a time, it results in the production of comparatively stable intermediates. One electron reduction of oxygen produces negatively charged superoxide (O2 −) which is the precursor of most of the ROS and plays very important role in oxidative chain reactions as a mediator. Hydrogen peroxide (H2O2) is produced when anion superoxide is dismutated by enzyme superoxide dismutase. Subsequently, H2O2 is either partly reduced to hydroxyl radicals (OH*) which is one of strongest oxidant molecules found in nature or it is fully reduced to water. Production of OH* is carried out by reduced transition metals which may be reduced again by O2 −*, continuing this process (YOURS et al. 1999). Furthermore, O2 –* may react with other free radicals such as nitric oxide (NO*) to produce peroxynitrite which is also a powerful oxidant. Among several types of ROS, superoxides (O2 −), hydroxyl radicals (*OH) and hydrogen peroxide (H2O2) are most studied ROS in cancer research.
Production of ROS in biological systems and their cellular detoxification
ROS are produced as a result of metabolism of oxygen in living organisms, and play significant role in cell signaling and homeostasis. Normally, ROS balance is maintained to prevent cell damage. But some environmental sources such as ultraviolet rays or exposure to heat can lead to increase in ROS levels. This condition is referred to as oxidative stress. In cancerous cells, several factors including increased metabolic activities, dysfunction of mitochondria, increased cell signaling, elevated peroxisome activity, and activity of oncogenes may result in the elevated level of ROS (Babior 1999; Storz 2005; Szatrowski and Nathan 1991). ROS are produced in mitochondria as a result of oxidative phosphorylation. Electron transport chain (ETC) consists of complexes I–IV and an enzyme ATP synthase found on the inner mitochondrial membrane. Superoxides (O2−) are produced at complexes I and III and approximately 80% of them is released into the intermembrane space while 20% into mitochondrial matrix (Derick et al. 2001). O2− is leaked into cytoplasm via outer mitochondrial membrane through mitochondrial permeability transition pore (MPTP) (Crompton 1999). Then, superoxide is dismutated to hydrogen peroxide (H2O2) either in cytosol by Cu/ZnSOD or in the mitochondrial matrix by MnSOD. H2O2 acts as second messenger and diffuses very rapidly. Recent research has shown that H2O2 can pass through cellular membranes through aquaporins (Bienert et al. 2007). For instance, aquaporin-8 was identified in inner mitochondrial membrane and suggested to have potential to serve as a channel for H2O2 (Lee and Thévenod 2006). Beside mitochondria, peroxisomes are another major site of ROS production (Dansen and Wirtz 2001). Xanthine oxidase (XOD) in the peroxisomal matrix and the peroxisomal membrane is generator of O2− and H2O2.
Growth factors and cytokines increase the generation of ROS to employ their effects in cancer. For example, treatment of cancer cells with interferon γ led to rise in levels of hydrogen peroxide and nitrite oxide (Lo and Cruz 1995; Tiku et al. 1990). Moreover, epidermal growth factor (EGF), tumor necrosis factor α (TNFα), lysophosphatidic acid, platelet derived growth factor (PDGF) and angiotensin all stimulate production of superoxide (Bae et al. 2000; Chen et al. 1995; Griendling et al. 1994; Meier et al. 1989; Ohba et al. 1994; Roy et al. 2006; Sundaresan et al. 1995). Oncogenic mutation of RhoGTPase K-ras is suggested to be linked with elevated production of superoxide causing several types of cancer (Aunoble et al. 2000; Minamoto et al. 1999, 2002). Superoxide level in cell is raised by growth factors and mutated K-ras either through NADPH oxidase or mitochondria, depending on the cellular environment (Storz 2005).
Cellular detoxification of ROS is carried out by certain enzymes and non-enzymatic molecules such as glutathione, flavonoids and vitamin A, C and E (Fig. 1). Besides, superoxide dismutase (SOD) is metal ion containing enzyme which synthesizes oxygen and H2O2 from negatively charged O2− by utilizing metal ions such as copper (Cu2+), iron (Fe2+) or zinc (Zn2+) as co factors. Various SODs are found in different locations of cell and are very specific in regulating biological pathways. Catalase catalyzes the breakdown of H2O2 to water and oxygen. In eukaryotes, its main location is cytosol and peroxisomes. H2O2 and peroxynitrite are reduced by a special type of thioredoxin peroxidases known as peroxiredoxins. There are two cysteine residues in active site of thioredoxin (Trx) which are convertible in reduced dithiol and oxidized disulfide forms (Holmgren 1995). When Trx is active, it hunts ROS and keeps proteins in reduced form. Thioredoxin reductase (TrxR) reproduces Trx by gaining electrons from nicotineamide adenine dinucleotide phosphate (NADPH) (Mustacich and Powis 2000). Glutathione system comprises glutathione (GSH), glutathione peroxidase (GPX), glutathione S transferase (GST), and glutathione reductase. GSH reduce disulfide bridges of cytoplasmic proteins to cysteines, thereby protecting tissues from oxidative stress. Concurrently, it is converted to glutathione disulfide (GSSG) by oxidation. GPX scavenges H2O2 and regenerates GSH by reducing GSSG (Carlberg and Mannervik 1975). GST facilitates the combining of GSH to numerous electrophilic molecules (Hayes et al. 2005; Sharma et al. 2004). GST levels are high in a wide range of tumors to control different pathways and also play a role development of chemotherapeutic resistance (Townsend and Tew 2003).
Failure of antioxidant agents to detoxify ROS leads to oxidative stress which can disrupt structure of biomolecules such as proteins, lipids and DNA. This result in serious damage to cells, including chromosomal abrasions, epigenetic dysregulation, and cell cycle deregulation. If left unchecked, these damages may eventually elicit clinical ailments such as autoimmune disorders, cardiovascular diseases neurodegenerative disorders and cancer (D’Autréaux and Toledano 2007; Fruehauf and Meyskens 2007). ROS aid cancerous cells in several processes such as survival, angiogenesis and metastasis. ROS are therefore held responsible for origination, growth, invasion and metastasis of cancerous cells (Clerkin et al. 2008; Giles 2006; Wu and Hua 2007). Paradoxically, ROS generation is a common approach shared by most of the anticancer strategies such as chemotherapy, radiotherapy and photodynamic therapy because of their involvement in cell death (Ozben 2007; Toler et al. 2006). ROS are used as tumor suppressing agents in cancer treatment. Due to double edged sword character of ROS in deciding cell survival, ROS level elevating and lowering strategies have been suggested for cancer treatment (Hyoudou et al. 2006, 2008; Ozben 2007). Both of these strategies are being used to develop various medicines, agents and methods, and a number of them have shown great anticancer potential in clinical trials. Due to complicated role of ROS in cancerous and non-cancerous cells, both pro and anti-oxidant approaches have shown complex benefits and disadvantages. This review targets the current situation of different approaches used to target cancerous cells via ROS.
The double edged sword function of ROS
A modest elevation in level of cellular ROS may induce cellular propagation and survival. Conversely, when the level of ROS reaches toxic threshold, it overcome antioxidant system of the cell and can cause cell death. Normal cells sustain redox balance by maintaining the balance between ROS production and elimination. Under physiological conditions, cells can withstand certain level of oxidative stress due to their conserved antioxidant system. In cancerous cells, increase in ROS production due to increased signaling cascades and metabolic activities may promote a ROS adaptation reaction, consequently causing upregulation of cellular antioxidants to maintain redox homeostasis. Therefore, susceptibility to exogenous ROS-producing agents that block the cellular antioxidants increases as cancer cells become more reliant on cellular antioxidants to deal with increased oxidative stress. At this stage, cell death in cancer cells can be induced by using exogenous ROS-generating agents that increase ROS stress. On the other hand, elevated levels of ROS play a vital role in carcinogenesis, tumor metastasis, and upkeep of phenotypical characteristics of cancer cells. By increasing intake of dietary antioxidants, increasing cellular antioxidants, and targeting sources of ROS, oxidative stress can be depleted, subsequently causing growth inhibition and increased susceptibility to cell death in cancer cells. This might set up a biochemical base to develop anticancer therapeutics via ROS-derived killing of cancer cells (Fig. 2).
Reasons for ROS scavenging anticancer therapy
ROS has role in cancer initiation, development and maintenance of phenotypical characteristics of cancer cells. Increased ROS generation in tumor cells compared to their normal counterpart is due to involvement of oncogenes which are also involved in malignant transformation. The relationship of rise in ROS levels and activation of oncogenes is still uncertain. In case of certain malignancies, such as lung and oral carcinomas, inflammation plays an etiological role. However, the stress induces ROS generation that cause chronic inflammation. Another most commonly implicated mechanism is oxidative DNA damage. Along with oxidative DNA damage, ROS can initiate different signaling pathways related to persistent survival of tumor, metastasis, vascularization, and proliferation in cancerous cells, which can stimulate cancer development (Halliwell 2007). Increased ROS production in tumors is linked to ischemic conditions and increased metabolic activities.
ROS and DNA damage
Oxidative DNA damage and genomic instability is common hallmark of all types of carcinogenesis, and mutations in a key nucleotide sequence in the DNA can lead to expression of malignant phenotypes. ROS can modify nucleotides and chromatin proteins, inducing mutations in DNA which may lead to cancer (Fruehauf and Meyskens 2007). For instance, hydroxyl radicals can result in point mutation by reacting with guanine to produce 8-hydroxy-2′-deoxyadensoine. This is one of the most dominant proofs of involvement of oxidative stress in cancer (Halliwell 2007). DNA fragmentation was induced in rat pancreas-derived acinar cells by glucose oxidase-mediated generation of H2O2. In pancreatic tumors, H2O2 can induce double strand breaks (DSBs) in the DNA. These in vitro results are supported by data obtained from patients of pancreatic ductal adenocarcinoma (PDA). Increased DNA adduct formation and oxidative DNA damage was found in PDA cells as compared to the normal pancreatic cells. In human-derived PDA cells, it may be hypothesized that NOX-mediated ROS generation facilitates oxidative DNA damage, as the production of NOX4 in PanIN and metastatic PDA which was supported by the same staining result to that of yH2AX, a DSB indicating marker.
ROS-induced mitochondrial DNA (mitDNA) mutations have recently been proved to mediate carcinogenesis (Fruehauf and Meyskens 2007). Linkage of ROS-derived DNA damage with cancer development is still controversial (Halliwell 2007). Nonetheless, pro-cancer roles of ROS are not due to increased ROS-induced DNA damage. For example, oxidative damage is more likely to occur in small intestine (SI) as compare to large intestine (LI) but carcinogenesis in LI is more common (Hong et al. 2005). Based on these studies, it is clear that ROS can induce significant DNA damage leading to harmful mutations an ultimately, carcinogenesis.
ROS and tumor proliferation
Due to boosted level of growth factors and signaling pathways of cellular proliferation, cancer cells have rapid growth rate. ROS can promote cell growth contributing to carcinogenesis by influencing any of these two factors (Pelicano et al. 2004). In a variety of cancer cell type, exogenous administration of ROS especially H2O2 or endogenous oncogene-mediated ROS generation increase proliferation by promoting pro-proliferative signaling cascades such as mitogen activated kinase (MAPK)/extracellular signal regulated kinase (ERK). ROS activates mitogen-mediated signaling cascades by inhibiting the action of MAPK phosphatases via oxidation of cysteine residues in the active site. ROS-facilitated tumor proliferation has been observed in numerous types of cancers such as breast cancer, lung cancer, and liver cancer, and has been depleted by the administration of antioxidants (Glasauer and Chandel 2014).
Signaling of growth factor receptors is inhibited by protein tyrosine phosphatase (PTP) and ubiquitin-derived inactivation. ROS can relieve both of them by oxidizing cysteine residues which are present in active sites of PTP and ubiquitin ligase (Chan et al. 2008; Chiarugi 2005; Ravid et al. 2004). Therefore, ROS can enhance the proliferation of cancer cells by prolonging activation of growth factors. In addition, cellular signaling factors are also regulated by ROS. For example, ERK1/2 is negatively regulated as phosphatase 3 (MKP3) is degraded due to increase in ROS levels during ovarian cancer. Subsequently, ERK1/2 is activated aberrantly and leads to carcinogenesis in ovary. Transcription factors including nuclear factor-κB (NFκB) and activator protein-1 (AP1) which are involved in expression of cell proliferation genes during cancer development are activated by raised levels of ROS. Furthermore, ROS produced by mitochondria are required the growth of KRAS lung carcinoma cell lines by modulation of MAPK/ERK signaling cascades. In summary, ROS scavenging can deplete the proliferation capability of tumor cells which may be achieved via ROS scavenging approaches.
ROS and angiogenesis and metastasis
Angiogenesis and metastasis of cancer cells are interconnected processes and lead to the final stage of malignancy. To fulfil the increased demand of oxygen and nutrients for continues growth of cancer cells, tumors are vascularized by angiogenesis. During the development of tumors, ROS especially H2O2 play an important role in vascularization by increasing activation of vascular endothelial growth factor (VEGF), a key growth factor for angiogenesis, and matrix proteins (Meng et al. 2002). In endothelial cells, the major source of ROS is NADPH oxidase. It is involved in increasing expression of hypoxia inducible factor 1α (HIF 1α). It is experimentally proven that NADPH oxidase 4 (NOX4) knockdown reduces VEGF and HIF 1α levels in ovarian tumors (Kizaki et al. 2006). Mitochondrial ROS play a key role in maintenance of HIF 1α as ROS production failure leads to inhibition of HIF 1α. But it is still controversial whether mitochondria-derived ROS is involved in cancer angiogenesis (Ushio-Fukai and Nakamura 2008).
Metastasis requires degradation of extracellular matrix, epithelial to mesenchymal transition (EMT), increased rate of migration, and several other intracellular adaptations. Increased ROS is directly associated with metastatic ability of tumors in numerous types of cancer such as breast cancer, prostate cancer and melanoma via regulation of certain key players in signaling cascades such as MAPK and HIFs (Lim et al. 2005). Exogenous ROS generating agents boost different levels of metastasis (Jing et al. 2002), whereas antioxidant therapy can weaken metastatic ability of cancerous cells (Ferraro et al. 2006). Surgery, a major approach for treating cancer, can increase metastatic progression of cancer cells by ROS production (Hyoudou et al. 2006). In vitro studies have revealed the possible ways which include abnormal production of integrins and matrix metalloproteinases (MMPs), and inhibition of anoikis (Halliwell 2007). Ishikawa et al., have confirmed the association of ROS with cancer metastasis. A poor metastatic cancer cell line became highly metastatic when its mtDNA was replaced with mtDNA taken from a very metastatic mouse cancer cell culture. The inserted mtDNA had mutations causing a defect in respiratory complex I and are linked with increased generation of ROS. Pretreatment of metastatic cancer cells with antioxidants inhibit their metastatic ability in mice (Ishikawa et al. 2008). ROS can also affect the structural components of cancer cells such as invadopodia, a microdomain involved in stimulation of cancer cell metastasis. Moreover, ROS also mediate the activation of MMPs which facilitate metastasis by degradation of cell membrane. Taken together, these ROS-modulated events lead to angiogenesis and metastasis in cancer cells which can be disrupted by implication of ROS-scavenging anticancer therapy.
Various ROS scavenging anticancer approaches
Because of important role of ROS in the development of tumor and its malignant phenotypical characteristics, treating ROS-triggered diseases, for instance cancer, has long been acknowledged as a therapeutic strategy (Kong and Lillehei 1998). Green tea polyphenols and red wine are two of the most suggested dietetic antioxidants for cancer avoidance (Bianchini and Vainio 2003; Siddiqui et al. 2006). Recently they are verified as promising anti-angiogenic agents in cancer therapy (Clerkin et al. 2008). Nevertheless, consumption of antioxidant supplements is getting consideration as epidemiological investigations link intake of different antioxidants with increased death rate in some populations, and the unavailability of sufficient data for preventing cancer, at least in societies with satisfactory routine diet (Seifried et al. 2007). Besides dietary antioxidants, numerous other therapies have been developed to target cancer through scavenging ROS (Table 1).
Taking dietary antioxidants
The consumption of dietary antioxidants as anticancer therapy has become extensive since 1980s. ROS can directly induce single stranded- or DSBs in the DNA, modifications in the nucleotides, and cross-link DNA, which may lead to cancer initiation, tumor metastasis and angiogenesis (Stewart and Wild 2014). There are numerous dietary vitamins and minerals that play a key role in maintaining and boosting the cellular antioxidant system, and etiology of the carcinogenesis. These mainly include vitamin C (ascorbate), vitamin E, vitamin A and selenium.
Vitamin C (ascorbate) is a water soluble antioxidant that has four types including ascorbyl radicals, ascorbic acid, dehydroascorbic acid (DHA) and ascorbate (Kontek et al. 2013). Its major anticancer properties include antioxidant activity, induction of apoptotic cell death, regulation of miRNA, inhibition of DNA methyl transferase (DNMT) and histone deacetylase (HDAC), and disruption of function of matrix metalloproteinases (Wu et al. 2017). Various studies have indicated that ascorbate can deplete the growth of different types of cancer cell lines in vitro even in millimolar concentrations (Boyacioglu et al. 2014; Hierro et al. 2014; Lum et al. 2016). Supplementation of ascorbic acid in combination with other vitamins induces necrosis-like cytotoxicity. In addition, vitamin C promotes apoptotic cell death by increasing the expression of tumor suppressor gene p53, and apoptosis-inducing protein, Bax (Shinozaki et al. 2011). It prevents oxidative DNA damage when its intake is close the current dietary recommendations for the UK and the USA (Wu et al. 2017). A polymorphic vitamin C transporter solute carrier family 23 member 2 (SLC23A2) has been identified that affects the risk factors for head and neck squamous cell carcinoma (HNSCC) linked human papillomavirus type 16 (HPV16) (Wu et al. 2017). Reduction of incidence of colorectal adenoma can be associated with genetic variation between solute carrier family 23 member 1 (SLC23A1) and SLC23A2 (Wu et al. 2017). Relationship between risk of gastric cancer and single nucleotide polymorphism (SNP) in SLC23A2 has also been suggested (Wright et al. 2009). Similarly, a more recent study by Minegaki et al. (2014) showed a linkage between risk of esophageal squamous cell carcinoma (ESCC) and SL23A2 genes. All of these findings are indicative of strong anticancer potential of vitamin C, which may be used during ROS scavenging anticancer therapy.
Naturally occurring vitamin E (Alpha tocopherol) comprises of eight lipophilic molecules that have remarkable antioxidant properties (Cardenas and Ghosh 2013; Jiang 2014). It disrupts ROS generation during oxidation of fats, thereby limiting production of free radicals. It can prevent the formation of potential carcinogenic nitrosamines from food in the stomach, and has the ability to perform immunostimulative function against cancer. However, relationship between intake of vitamin E and incidence of nonsmall cancer has not been much studied in epidemiological perspective. A study involving women aged 45 years or older who were given 66 International Unit (IU) vitamin E supplement each other day for 10 years showed that intake of vitamin E had no effect on risk of developing cancer (Ho et al. 2015). Two recent studies investigated whether intake of vitamin E affected the incidence of prostate cancer (Albanes et al. 2014; Kim et al. 2015). Albanes et al. concluded that there is no relationship between dietary vitamin E intake and risk of development of prostate cancer (Albanes et al. 2014). Whereas the risk of prostate cancer was reduced by 32% in male smokers who were given 50 IUI of vitamin E for 5–8 years as compared to the subjects who did not take supplementation (Kim et al. 2015). Another investigation in Iowa proved that higher intake of vitamin E could significantly reduce the risk of development of colon cancer, particularly in women aged less than 65 years (Li et al. 2015). Likewise, another study provided the evidence that intake of 400 IU of vitamin E can dramatically reduce the risk of bladder cancer (Mazdak and Zia 2012). Based on these studies, it can be suggested that the risk of development of cancer can be reduced by intake of vitamin E and it may also have implications during anticancer therapy.
Selenium exists in four forms; selenomethionine, selenocysteine, selenite and selenite (Cornelis et al. 2014). The most common form of selenium in human cells is selenomethionine. Selenium plays a vital role in DNA synthesis, various metabolic reactions, and prevention of oxidative cellular damage (Li et al. 2014). Due to its antioxidant, apoptosis inducing, antiangiogenic, and immune system regulating properties and its involvement in DNA synthesis and repair, it play a vital role in prevention of cancer (Combs 2015; Jablonska and Vinceti 2015; Weekley et al. 2013). Selenium induces programmed cell death (PCD) by a variety of mechanisms. Selenite promotes caspase-independent apoptotic cell death in cervical tumors through expression of p53 and p38, and production of O2−, induction of ER stress and consequent p53-mediated apoptotic cell death in prostate tumors (Wu et al. 2017). Selenite has been reported to mediate apoptosis in promyelocytic leukemia tumors via inhibition of autophagy by PI3K/Akt signaling cascade (Wu et al. 2017). Epidemiological investigations have indicated a negative relationship between concentration of selenium and incidence of esophageal, skin, lung, bladder and gastric cancers. Findings from 20 epidemiological investigations with total 13,254 subjects indicated a positive relationship between plasma selenium concentration and reduced risk of prostate cancer (Hurst et al. 2012). Contradictory results have been yielded from randomized controlled study trials of selenium intake for prevention and treatment of cancer. Findings from nine randomized controlled trials indicated that selenium supplementation might prevent gastrointestinal cancers. A secondary analysis in Nutritional Prevention of Cancer trial involved 1312 subjects with the history of squamous cell and basal cell carcinomas of skin revealed that the risk of prostate cancer was lowered by 52–65% after supplementation of 200 μg of selenium per day for 6 years. In addition, this effect was strongest in male subjects with baseline prostate specific antigen concentration of 4 ng/mL or less (Outzen et al. 2016). Cochrane et al. reviewed the relationship of selenium and cancer prevention, demonstrating decrease in the risk of cancer development by 31%, reduce by 45% in cancer mortality rate, and decrease in risk of bladder cancer by 33% and in men, a decrease in the risk of development of prostate cancer by 22% (Reid et al. 2008). However, the investigation did not show that there is an association between intake of selenium supplements and risk of breast cancer development. To conclude, supplementation of selenium may decrease the risk of cancer development significantly and may also be used during anticancer therapy.
Beside the benefits of antioxidant intake, there are various disadvantages particularly with reference to use of vitamin C and E, β-carotene and selenium (Seifried et al. 2007). Main concern is about the damaging effects of dietary antioxidants on ROS levels when accurate regulation of ROS is required to aid cells function normally or to cause apoptosis in tumor cells (Seifried et al. 2007). The intake of antioxidant agents during cancer treatment is also getting attention. Some studies show that antioxidants can enhance harmful effects of treatment, however, others indicate that antioxidants hinder the activity of anticancer therapies which depend on ROS to cause cell death in cancer cells (Conklin 2000; Seifried et al. 2003). Preclinical findings are inadequate to tackle this problem, though some clinical studies have shown that there is no benefit of intake of antioxidants during anticancer therapy (D’Andrea 2005). Therefore, cancer patients should be careful about supplementation of dietetic antioxidants during anticancer treatment until the emergence of conclusive clinical results about the benefits of consuming dietary antioxidants alongside chemotherapy or radiotherapy.
Targeting NADPH oxidase
ROS production is the primary and sole function of NADPH oxidase and play important role in oxidative stress. Blocking this function of NADPH can result in disruption of a major source of ROS in cellular environment. There are several agents including conventional small molecules and novel small molecules, and biologicals which are being used as NADPH oxidase inhibitors.
Several small molecules have been evaluated for inhibition of NADPH oxidase. Majority of these agents are not specific as they block the action of several other ROS generating enzymes along with NADPH oxidase. Most commonly used NADPH inhibitors include diphenylene iodonium (DPI) and apocynin (Altenhöfer et al. 2015). Generally, DPI blocks flavoprotein and also inhibits XOD and proteins of mitochondrial ETC (Altenhöfer et al. 2015). On the other hand, apocynin acts as antioxidant, thereby, scavenges ROS, and it also inhibits Rho kinases (Yoshida et al. 2017). 4-(2-Aminoethyl)-benzenesulphonyl fluoride (AEBSF) and plumbagin are also used as NADPH inhibitors but they have off-target effects. For instance, AEBSF blocks serine proteases and plumbagin inhibits NF-kappa-B and acts as bactericidal (Altenhöfer et al. 2015; Padhye et al. 2012). Two another inhibitors GKT136901 and GKT137831 are developed by GenKyoTex which inhibit NOX1, NOX4 and NADPH oxidase 5 (NOX5) (Altenhöfer et al. 2015). GKT136901 shows antioxidant activity by scavenging peroxynitrite, a ROS, produced by reaction of NO* with O2 − while GKT137831 is not tested yet for this type of antioxidant properties (Schildknecht et al. 2013). Similarly, The Scripps Research Institute evaluated 16,000 compounds for inhibition of NOX1 and identified 2-acetylphenothiazine (ML171) as a potential NOX1 inhibitor (Gianni et al. 2010). It indicated IC50 value of 130–250 nM for NOX1 and 3–5 mM for NOX2-4 as well as XOD (Gianni et al. 2010). In conclusion, conventional NADPH oxidase inhibitors are not much specific and their administration does not assure the activity of NADPH oxidase in a living system. Conversely, novel small molecules are more specific than historical NADPH oxidase inhibitors but they need more in vivo evaluation.
Biologicals as therapeutic molecules include activity modulating antibodies and peptides. Only a couple of antibodies have been suggested to inhibit NOX2 and NOX4 but none of them has been tested in experiment and fully evaluated as biologicals against different forms of NADPH oxidase (Zhang et al. 2011). Peptides face hurdles while being used as inhibitors because they stimulate potential immune responses, show less in vitro stability, and failure to pass through cell membranes. Several peptides have been synthesized but only a few of them which target FAD and NADPH binding structural domains of NOX2 inhibited NADPH oxidase. NOX2 docking sequence (NOX2ds)-tat is the first rationally synthesized NOX inhibitor. It binds to p47, a structural protein of NOX complex and inhibits formation of functional NOX2 complex (Altenhöfer et al. 2015). In summary, very less or no data is available involving biologicals to inhibit NADPH oxidases such as NOX3 and NOX5. While NOX2ds-tat can be administrated to investigate the role of NOX in acute stage of cancer.
A recently developed nitrogen-derived bisphosphonate, minodronate, completely blocks VEGF signaling cascade by inhibiting NADPH oxidase-facilitated ROS production in endothelial cells via suppression of geranylgeranylation of Rac, a structural part of NADPH oxidase (Fruehauf and Meyskens 2007; Yamagishi et al. 2004). Clinical trials and studies in mice models have validated the efficiency of minodronate in curing bone metastases from breast cancer (Kubo et al. 2006; Sato et al. 2006). Immuno-improving characteristics of histamine together with IL-2 and INF-α to promote cytotoxicity in human cancers also depend on inhibition of NADPH oxidase. In this way, histamine prevents ROS-stimulated cell death in NK cells and T cells and also sustains their activation by different cytokines including IL-2 used in immune system dependent anticancer treatments (Hellstrand 2002). Phase III clinical trials for the treatment of acute myeloid leukemia (AML) and myeloma have proved its efficacy in cancer treatments (Agarwala and Sabbagh 2001). To conclude, NADPH oxidase inhibition can play a very vital role in cancer therapy and investigation of function of NADPH oxidase in carcinogenesis.
Boosting antioxidant enzymes
Increasing GSH, GST, SOD, GPX, and catalase expression inhibit cancer development (Liu et al. 2006; Nelson et al. 2006; Venkataraman et al. 2005). These studies support the strategy of boosting ROS scavenging enzymes for anticancer therapy. But a few studies have been conducted to analyze the effect of upregulation of expression of cellular antioxidant enzymes and its correlation with anticancer therapy.
Direct clinical administration of GSH does not have any effect, and so, a wide range of GSH precursors or synthetic analogues have been developed in order to minimize GSH’s different pharmacological and physiological complexities. The first chemically modified analogue of GSH is N-acetylcysteine (NAC or mucomyst), and YM737 has been recently discovered (Traverso et al. 2013). Due to increased level of GST in resistant cancer cells, synthetic GSH analogues, which block GST isoforms, have been generated (Traverso et al. 2013). Telcyta (TLK-286), an analogue of GSH, is administered in combination with platinum- and taxanes-based chemotherapeutics in variety of cancer cells (Wu et al. 2010). NOV-002, an agent containing oxidized GSH, disturb the balanced ratio of GSH and GSSG and promotes S-glutathionylation (Fidias and Novello 2010). NOV-002-mediated S-glutathionylation growth, survival and metastasis of myeloid cancer cell lines and dramatically improved the efficacy of cyclophosphamide to treat colon cancer (Montero and Jassem 2011). Another therapeutic agent sulforaphane (SF) is the most powerful stimulator of NRF-2 and phase II antioxidant system (Traverso et al. 2013). It has potential anticancer and chemopreventive ability by promoting apoptotic cell death and cycle arrest. In contrast, inhibition of NRF-2 signaling cascades may increase the sensitivity of chemoresistant cancer cell to cytotoxic drugs. In this scenario, brusatol blocks this pathway and can be utilized to increase the efficacy of chemotherapy (Ren et al. 2011). Increasing levels of cellular GSH and its associated enzymes can maintain redox homeostasis and represents a strong potential as a cytoprotective approach against carcinogenesis.
A promising tumor targeted delivery system for SOD and catalase by PEG conjugation is recently developed (Hyoudou et al. 2006, 2008). The major localization of catalase is cytoplasmic membrane, especially of the cancer cells (Bauer 2012). Another study indicated that tumor development in vivo depends on resistance to exogenous ROS specifically H2O2 (Glorieux and Calderon 2017). Change in catalase concentration with increase in chemoresistance in tumors has also been reported (Glorieux and Calderon 2017). The potential of catalase for the development of chemoresistance in cancer cell was explored by its overproduction in MCF-7, a type of breast cancer cell line (Glorieux et al. 2011). No noticeable chemoresistance was developed catalase overexpressing cells but their resistance to pro-oxidant cytotoxicity induced by H2O2 was significantly increased (Glorieux et al. 2011). Based on these findings, novel anticancer therapeutics using upregulation of catalase expression can be developed. Under intense oxidative stress, cellular antioxidants play a key role in detoxifying ROS. Upregulation of cellular antioxidants can be a potential target to treat cancer by using anti-oxidant therapy.
Manipulating nitroxide derivatives
Nitroxide derivatives especially nitroxide-derived free radicals have distinct antioxidant and anticancer properties as they mediate metabolism of numerous ROS (Liu et al. 2013). Cyclic nitroxides are a diverse group of stable radicals that possess strong antioxidant properties. 4-Hydroxy-TEMPO or tempol is a heterocyclic nitroxide compound derived from triacetone amine which carries out the disproportionation of O2− and H2O2. It has excellent membrane permeability. It has been found to inhibit the tumor development in mice models by decreasing the total ROS production. It has also been demonstrated to modify the lead (Pb) derivatives for improvement of anticancer properties (Zhao et al. 2014). Introduction of Tempol into triazene derivatives (SLTA6) can increase the selective and preferential killing of melanoma B16 (Sun et al. 2016).
Adamantyl group is common in biologically active molecules. Numerous adamantyl-based drugs have been developed which play significant role in current anticancer treatments (Sun et al. 2016). Administration of adamantyl based drugs promotes lipophilicity and therefore, increases biological availability (Al-Abdullah et al. 2015). In addition, adamantyl group may also improve the therapeutic efficacy and selectivity of Pb-derivatives through variety of mechanisms (Sun et al. 2016).
Another compound aryloxyacetylaminobenzoic acid is a novel hypoxia inducible factor 1 (HIF1) blocker which inhibits HIF 1α in human Hep3B cells (Sun et al. 2016). Moreover, adamantyl-modified retinoid showed potential apoptotic-inducing and antiangiogenic activity in solid tumors (Sun et al. 2016). A series of nitroxide-based agents were generated by combination of active components of both adamantyl and Tempol which inhibited proliferation in human hepatocellular carcinoma (HCC) (Zhu et al. 2016). Recently, an agent named compound 4 was synthesized from adamantyl nitroxide and its antiproliferative activities on various types of HCC were evaluated. The anticancer activity of compound 4 was remarkable especially against Bel-7404 cells. It also reduced expression of Bcl-2 and promoted expression of Bax, therefore, confirming its effect on apoptosis in human HCC (Sun et al. 2016). In summary, nitroxide derivatives have strong anticancer and antioxidant potential but still there is a dire need of synthesis of nitroxide-based anticancer agents with improved efficacy to be productive in ROS scavenging anticancer therapy.
Reasons for ROS boosting anticancer therapy
Elevated ROS levels lead to cytotoxicity and reversing chemotherapy resistance in cancerous cells. Though curing ROS-derived cancers with antioxidant agents is rational, still the fundamental mode of action of chemotherapy and radiotherapy is not related with increase in antioxidants, rather it results in rise in ROS generation ultimately causing severe oxidative stress (Kong and Lillehei 1998). A wide range of investigations have suggested that increased ROS generation is the mechanism shared by numerous therapies and promoting more rise in ROS production levels can efficiently kill cancerous cells (Neumann and Fang 2007; Ozben 2007).
ROS-induced apoptosis
Major mechanism shared in common by chemotherapy and radiotherapy is ROS-induced apoptosis (Ivanova et al. 2012). Most of the recently developed anticancer drugs are reported to induce apoptotic cell death in tumor cells by the production of ROS (Díaz-Laviada and Rodríguez-Henche 2014; Shen et al. 2013; Tian et al. 2014; Zhu et al. 2014). A variety of mechanisms for explanation of ROS induced apoptosis have been put forward. Studies have shown that ROS mediates apoptosis by stimulating activity of caspases and upregulating death receptor 5 (DR5) (Chen 2014). Several signaling cascades such as MAPK pathway and ERK pathway are involved in ROS-induced apoptotic cell death (Chen 2014; Lee et al. 2012).
Apoptosis derived by death receptor and mitochondria depend on cellular ROS levels (Ozben 2007). Fas ligand (FasL) activates fast production of ROS which is mostly derivative of NADPH oxidase as an earlier event of Fas stimulation and apoptosis initiation. A PKCzeta-reliant phosphorylation of p47-phox promotes the activation of NADPH oxidase. FasL-activated ROS response is needed for epidermal growth factor receptor (EGFR) and Fas interaction as indicator of phosphorylation of Fas and tyronsine, which subsequently leads to initiation of apoptosis by recruiting Fas-linked death domain and caspase-8 (Medan et al. 2005; Reinehr et al. 2005; Uchikura et al. 2004). In addition, FasL-promoted ROS production aids ubiquitination followed by inhibition of function of FLICE inhibitory protein (FLIP) to assist activation of Fas (Wang et al. 2007).
Leakage of cytochrome c from permeability transition (PT) pore complex, apoptosome production and triggering of caspases are major events of mitochondrial-induced apoptosis. ROS affect the structural integrity of PT pore by signaling cascades and oxidative alteration of configuration of PT pores. Stress activated protein kinase (SAPKs) also known as c-Jun N-terminal kinase (JNK) activates ROS-promoted opening of PT pores (Benhar et al. 2002). ROS induce JNK signaling pathway via following processes. (1) To activate the apoptosis signal-regulating kinase 1 (ASK1). (2) To release Mitogen activated protein kinase kinasekinase 1 (MEKK1) from attaching with GST (Liu and Min 2002; Ryoo et al. 2004; Song and Lee 2003). (3) To block action of PTP to allow functioning of Src for the initiation of downstream signaling (Lee and Esselman 2002). Pore complex in inner and outer mitochondrial membrane is suggested to negligibly comprise of voltage dependent anion channel (VDAC), adenine nucleotide translocase (ANT) and cyclophilin-D (Brenner et al. 2005; Fruehauf and Meyskens 2007). Independent of aid of proapoptotic-Bcl-2 family proteins, superoxides promote apoptotic cell death by induction of VDAC-dependent permeability in outer membrane (Madesh and Hajnóczky 2001). In summary, boosting ROS can induce apoptotic cell death in cancer cells and this aspect can be therapeutically implicated via ROS boosting anticancer therapy.
ROS and autophagy
Autophagy, a process dealing with the degradation of proteins and organelles and their recycling for formation of new cells, play a key role in cellular reactions to increased ROS levels. Several studies reveal that autophagy is mediated and controlled by ROS (Scherz-Shouval and Elazar 2011; Scherz-Shouval et al. 2007a). The consequences of autophagy differ from infection-preventing elimination of pathogens, dysfunctioning cellular organelles, to cell death. Therefore, ROS can act as signaling molecules in survival prone autophagy (Scherz-Shouval and Elazar 2007). Application of ROS-derived autophagy in treating cancers has been recently started (Cai et al. 2008; Ghavami et al. 2008; Lim et al. 2005). Level of ROS production regulate induction of autophagy in cancer cells (Poillet-Perez et al. 2015). Oxidation of ATG4, an enzyme required for delipidation of ATG8 protein, by H2O2 is the prerequisite for induction of autophagy. This oxidation leads to inactivation of ATG4 resulting to elevated production of LC3-associated autophagosomes (Poillet-Perez et al. 2015). Indirectly, AMPK pathway is another mean for regulation of autophagy by ROS. Activation of AMPK induces autophagy by inhibiting the mammalian target of rapamycin complex 1 (mTORC1). Oxidative stress can affect AMPK pathway and can activate it by phosphorylating the AMPK kinase (AMPKK) followed by increased H2O2 production, which indirectly induces apoptosis (Poillet-Perez et al. 2015). ROS can also modulate autophagy by affecting the activity of various transcription factors such as NF-κB which results in expression of autophagy-associated genes (BECLIN1/ATG6 or SQSTM1/p62) in tumors (Boyer-Guittaut et al. 2014).
Efficacy and selectivity are specified for limited types of cancers together with those resulted from radiotherapy and chemotherapy resistant malignant glioma (Kim et al. 2007; Scherz-Shouval et al. 2007b). Selenite causes cytotoxicity-mediated autophagy in human glioma tumors and overproduction of SOD considerably inhibits selenite-derived autophagy (Kim et al. 2007). Small iRNA-facilitated knockout of autophagy related gene 6 (ATG6) or ATG7 lessens selenite-promoted autophagy. Based on these results, it can be concluded that increased production of ROS and its manipulation can induce autophagy in cancer cells.
ROS and chemo-resistance
ROS has been implicated in development of resistance to several types of chemotherapy since a long time (Chen 2014). ROS production in chemoresistant tumors is less than that in chemosensitive cells. A recent study involving siRNA knockdown showed that chemoresistant tumors have high activity of cellular antioxidants and low production of ROS than chemosensitive cancer cells (Chen 2014). In this scenario, ROS may contribute to chemosensitivity by inducing apoptotic cell death (Suzuki-Karasaki et al. 2014).
Low levels of glucose and decreased ROS scavenging capabilities of the cell may result in elevated production of ROS by mitochondrial ETC which induces cytotoxicity, mediates several signaling pathways, for instance ERK1/2, and increase expression of genes linked with malignancy in human chemoresistant breast carcinoma (Chen 2014). Conversely, 2-deoxy-d-glucose (2-DG) was suggested to promote chemoresistance in cancer cells via ROS-stimulated upregulation of production P-glycoprotein (Chen 2014). In addition, 2-DG may also induce chemoresistance in human ovarian carcinoma via upregulation of chemoresistance-linked target genes such as dihydrodiol dehydrogenases (DDHs). DDHs have also been proved to modulate the ROS production and development of cisplatin resistance in cancer cells (Chen 2014; Chen et al. 2008).
Elevated redox capability of GSH in tumors has been associated with resistance to chemotherapy since long time Traverso et al. (2013). Increased cellular redox causes more resistance to several chemotherapeutic agents, for instance adriamycin (Traverso et al. 2013). Moreover, NOX1 incorporation into prostate tumors could considerably reduce production of HIF-1α and P-glycoprotein (P-gp) which is responsible for multidrug resistance (MDR). Similarly, introduction of ROS-generating drug emodin could block HIF-1α and decrease MDR production, subsequently retaining increased level of doxorubicin (Chen 2014). These findings from preclinical and clinical studies indicate a negative association between ROS and resistance of cancer cells to chemotherapeutics.
Various ROS boosting anticancer approaches
Elevating ROS to target cancer cells can be achieved in two main ways: (1) using inhibitors of antioxidant system of cancerous cells and (2) promoting increased generation of ROS by exogenous agents.
The final concentration of ROS in tumors is crucial for ROS boosting anticancer therapy. It depend on ROS production mediators, distinctive ROS concentrations, and capability of anti-oxidants in cancerous cells. Ability of arsenic trioxide (ATO) to kill leukemia cells and sensitivity of leukemia cells to ATO depend on the inherent ROS concentrations in chronic lymphocyte leukemia (CLL) (Yi et al. 2002, 2004). Therefore, by measuring precise levels of ROS in leukemia cells, the sensitivity of pro-oxidant anticancer treatment can be predicted in CLL patients. Intensity of therapy may vary with respective level of ROS in tumors. Higher dose might be needed for patients with decreased ROS generation in cancer cells. Nevertheless, several metastatic tumors with strong antioxidant system that can defend themselves against intense oxidative stress might show a low concentration of ROS and increased resistance to chemotherapy. Agents attenuating antioxidant system might result in more efficient killing of such type of tumors.
Production of ROS directly in cancer cells
Several approaches have been developed based on this strategy, viz. administration of ROS and ROS producing agents to cancer cell cultures (Neumann and Fang 2007). For instance, H2O2 is injurious to human health. Several attempts have been made to develop agents that mediate conversion into ROS or promote intercellular ROS production in cancer cells. Some of these agents are under development while others have been approved as anticancer drugs (Tables 2, 3). These drugs are either used alone or together with radiotherapy and chemotherapy.
Majority of the chemotherapeutic drugs increase ROS production in cancer cell to induce their anticancer effect and, therefore, cause oxidative cellular damage (Glasauer and Chandel 2014). Some chemotherapeutic agents like taxanes, alkaloids, and antifolates induces mitochondria-mediated cytotoxicity and also interrupt the mitochondrial ETC resulting in elevated O2 − generation (Glasauer and Chandel 2014). Other chemotherapeutic drugs such as cisplatin and doxorubicin increases ROS production leading to cytotoxicity in cancer cells.
Procarbazine is the first ROS generating drug used in anticancer therapy (Renschler 2004). Its metabolism produces azo-derivatives leading to generation of ROS which results in severe oxidative DNA damage. Its first clinical trial was conducted in 1963 and it was approved as cytotoxic agent. Since then, it has been used for treating Hodgkin’s lymphoma and brain cancers (Renschler 2004). During the last decade, several conventional anticancer agents have been analyzed for their linkage with manipulation of ROS. For example, a ROS producing anthracycline doxorubicin is used for the treatment of Kaposi’s sarcoma (KS), acute lymphocytic leukemia (ALL), breast cancer and bladder cancer. Biologics can also promote apoptotic cell death by ROS generation. ROS dependent arsenic-derived drugs are used for the treatment of acute promyelocytic leukemia (APL). Imexon stimulate apoptosis by elevating oxidative stress. Preclinical and phase I/II clinical investigations have confirmed the anticancer ability and safety of imexon in leukemia (Engel and Evens 2005). In the meantime, various ROS-dependent anticancer agents are in under development. Mitochondria are the main source of superoxides. Numerous anticancer drugs have been noted to disrupt the ETC, resulting in raised electronic outflow and subsequently leading to increased ROS generation. Moreover, some ROS-generating drugs directly target complex I and II which are main components of ETC. Furthermore, ROS generation is also a source of ROS production (Chou et al. 2004). ATO, successful in treating APL patients, induces apoptotic cell death via ROS generation through NADPH oxidase (Chou et al. 2004).
A well-known side effect of chemotherapy is the extremely high production of ROS that induces cytotoxicity in normal cells. Also, chemotherapy is not specific, thereby it has off-target effects. Other promising ROS-based chemotherapeutics, which are more target-specific, have shown remarkable anticancer properties by inducing apoptotic cell death in cancer cells.
Modality photodynamic therapy (PDT) is recently approved for treatment of some types of cancer. It is developed on the base of generation of ROS after the stimulation of photosensitizer by light. Cancer cells preferentially take up porphyrin-precursor molecules, which are used as photosensitizer to produce cytotoxic molecular oxygen that leads to photooxidative stress in cancer cells. Other than induction of apoptotic cell death, PDT has various biological effects such inflammatory and immunological stimulation against oxidative stress of specific type of cancer cells (Sies et al. 2017). Molecular oxygen is the most useful ROS in PDT for promoting action of XOD and photo-oxidation of cellular components mediating ROS generation (Buytaert et al. 2007; Hsieh et al. 2003; Solban et al. 2006).
Some studies indicate that ROS generating drugs can increase the efficacy of conventional anticancer therapies in killing cancer cells (Pelicano et al. 2004; Wang and Yi 2008; Yi et al. 2004). Synergizing effect of emodin on various ROS-reliant chemotherapeutic agents has been shown in killing multiple types of tumors (Wang and Yi 2008). It causes very negligible damage to normal cells in vitro and exerts no noticeable toxic effect in mice. Inhibition of AP1, NFκB, and HIF-1α and stimulation of caspases are causal reasons for regulation of ROS in apoptotic cell death (Cai et al. 2008; Jing et al. 2006; Pelicano et al. 2004). Induction of growth inhibition and apoptosis, or reinstating anoikis can exert combined anticancer effect. In summary, chemotherapy and recently developed cancer specific PDT are novel approaches to promote the production of ROS in cancer cells.
Inhibition of antioxidant system in cancer cells
Besides elevating ROS generation directly, disrupting cellular antioxidant enzymes would also excessive ROS production ultimately triggering cell death in tumors. Glutathione system, Trx and SOD are the major targets of ROS boosting anticancer agents.
Nontrasformed cancer cells have less rate of ROS generation and, therefore, are less reliant on cellular antioxidants. Findings from several studies have indicated that inhibition of cellular antioxidant system induces ROS-facilitated cytotoxicity in numerous types of tumors (Glasauer and Chandel 2014; Glasauer et al. 2014). Phenethyl isothiocyanate (PEITC) combined with GSH deplets the GSH pool, resulting in cellular oxidative stress and cytotoxicity in cancer cells. Moreover, it blocks GPX and induces cell death in HRAS-transformed ovarian carcinoma. It has also been proved to increase survival in ovarian carcinoma xenograft (Glasauer and Chandel 2014).
Increased activity of GSH and GST is involved in development of resistance to chemotherapy in cancer cells. The cytotoxic ability of platinum derived agents, alkylating agents, and arsenic derivatives can be restored by the reduction of GSH levels. To overcome the resistance to anticancer drugs, several chemotherapeutic compounds targeting cellular GSH levels have been developed. Beta phenylethylisothiocyanate (PIETC) can block GPX and lessens GSH levels ultimately causing high ROS generation in malignant cancer cells (Trachootham et al. 2006). Buthioninesulfoximine (BSO) prevents production of GSH and has been studied well in increasing sensitivity of tumors to a variety of drugs (Renschler 2004). Synergetic effect of BSO and ATO can induce apoptosis in APL tumors with depleted GSH levels (Dai et al. 1999; Dansen and Wirtz 2001). Likewise, a copper (Cu) derivative, copper N-glycinate (CuNG) is demonstrated to promote ROS production by targeting GSH enzyme to increase sensitivity to chemotherapy in Ehrlich ascites carcinoma tumors (Mookerjee et al. 2006).
Trx and TrxR is a suitable target for developing novel anticancer drugs due to following reasons. (1) Overproduction of Trx and TrxR has been linked to chemotherapeutic resistance, malignant tumor growth and less survival (Biaglow and Miller 2005; Hong et al. 2005). (2) Trx is involved in blockage of PT pore complex to maintain level of ANT (Fruehauf and Meyskens 2007). (3) Reversion of morphological characteristics of mouse lung carcinoma (LLC1) and reduction of tumor metastasis by TrxR1 knockdown is also reported (Tobe et al. 2012). Numerous compounds targeting Trx system are being analyzed in investigational cancer models. For instance, motexafin gadolinium, a Trx-blocker can precisely and favorably target cancer cells is in phase III clinical trials (Biaglow and Miller 2005).
SOD1 can be targeted to preferentially kill several types of tumor cells. Malignant carcinoma depends on SOD to modulate ROS production. A study involving utilization of a small molecule for targeting SOD1 showed that its inhibition led to the prevention of growth of KRAS-mutatnt lung adenocarcinoma in vitro (Glasauer and Chandel 2014). Likewise, NRF2, a key regulator of cellular antioxdiants, may be targeted for ROS boosting anticancer therapy. Oncogenes such as KRAS and MYC mediate the activity of NRF2. Mutagenesis in NRF2 in various types of cancers lead to transcription activity of NRF2 (Glasauer and Chandel 2014; Jaramillo and Zhang 2013; Kansanen et al. 2013). Therefore, NRF2 inhibition can be therapeutically targeted to promote ROS-induced cell death in cancer cells.
Elevated superoxide generation and depleted SOD levels in tumors may render the SOD-dependent malignant carcinoma. Inhibition of SOD may be a favorable approach for preferential targeting of tumors. Potential of a recently developed anticancer drug methoxyestradiol (2-ME) to block SOD and stimulate apoptosis in leukemia cells via a ROS-facilitated mechanism has been verified. Disruption of activity of Cu, Zn-dependent SOD by copper chelating agents, for instance Disulfiram and ATN224 has been demonstrated in clinical trials. In summary, cellular antioxidant system represents a potential therapeutic target for ROS boosting anticancer therapy and can be implicated to induce cytotoxicity in numerous types of tumors.
The role of microbiota in ROS-dependent cancer therapy
Human microbiota is composed of bacteria, archaea, human viruses, fungi, and protozoa that occupy epithelial barrier surfaces of human body (Costello et al. 2012). Commensal microbiota is essential for health and survival of an organism. Microbiota plays an important role in regulation of several physiological functions such as metabolic pathways, neurological functions, and inflammation and host immunity (Dzutsev et al. 2015). Systemic functions such as adaptive immunity of the epithelial barriers which acts as reservoir of microbiota are also affected by commensal microbiota. In addition, it also modulates cancer initiation, development and response to anticancer therapeutics (Dzutsev et al. 2015; Roy and Trinchieri 2017). Studies in a past few years have validated the effect of microbiota on anticancer ability and efficacy of various anticancer approaches (Dzutsev et al. 2015; Goldszmid et al. 2015; Iida et al. 2013; Perez-Chanona and Trinchieri 2016; Roy and Trinchieri 2017; Zitvogel et al. 2015). Commensal microbiota affect the response to chemotherapy and radiotherapy by regulating various cellular functions performed by myeloid cells in the tumor microenvironment (Goldszmid et al. 2015; Iida et al. 2013). Despite recent advances in various ROS-dependent anticancer approaches such as chemotherapy and radiotherapy, a large number of patients still do not respond to cancer treatment.
Microbiota and ROS-dependent chemotherapy
Majority of the chemotherapeutic agents kill cancer cells by targeting DNA and cell division. Toxic effects of chemotherapy on other cellular components such as cell membrane and mitochondria may also lead to cytotoxicity (Sancho-Martínez et al. 2012). The specificity of chemotherapy largely depends on the rate of cell division so it induces significant cytotoxicity in tissues having high rate of cell division. Moreover, its toxicity is associated for cells that have a high rate of cell division (Roy and Trinchieri 2017).
Several platinum-derived chemotherapeutic agents such as oxaliplatin and cisplatin induce cytotoxicity by blocking DNA replication and cellular compartments including mitochondria and cell membrane (Galluzzi et al. 2014). They result in DSBs in the DNA by forming platinum–DNA adducts. Besides anticancer activity, platinum-derived chemotherapeutic agents also cause toxicity in intestine and nephron, disruption of structural conformation of blood–brain barrier, and ototoxicity (Park et al. 2013; Roy et al. 2013; Zhu et al. 2015). Platinum-based chemotherapeutics disrupt barrier functions by killing regenerating mucosal cells of intestine. They lead to septicaemia and inflammation by disruption of barrier functions that enables commensal microbiota to interfere with the blood circulation and lymphatic system (Roy and Trinchieri 2017). The anticancer activity of oxaliplatin and cisplatin on subcutaneous tumors in mice treated with broad-spectrum antibiotics to deplete their commensal microbiota is decreased significantly (Iida et al. 2013). The level of inflammatory gene expression in microbiota-depleted mice induced by oxaliplatin is lower than that of normal mice (Iida et al. 2013). Key cytotoxicity-inducer components of platinum-derived drugs that initiate are ROS (Dasari and Tchounwou 2014). Interaction of cancer cells with drugs was suggested to be the source of ROS which leads to oxidative DNA damage and apoptosis in cancer cells. Conversely, the depletion of commensal microbiota in mice inhibited paracrine generation of ROS by tumor-penetrating myeloid cells through NADPH oxidase 2 (NOX2) (Roy and Trinchieri 2017). The anticancer effect of oxaliplatin is dramatically reduced in Cytochrome B-245 Beta Chain (CYBB)-deficient mice or in mice treated with broad-spectrum antibiotics (Iida et al. 2013). Likewise, re-association of microbiota-depleted mice with probiotic bacterium Lactobacillus acidophilus reinstates anticancer effect of cisplatin and restores gene expression involved in inflammation (Gui et al. 2015). The underlying mechanism of interaction of gut microbiota with intratumoral myeloid cells for ROS generation during treatment with platinum-based chemotherapeutics relies on signaling cascades via myeloid-differentiation primary response 88 (MYD88)-linked pattern recognition receptors (PRRs) (Iida et al. 2013).
Very less data are available about the potential of probiotic bacterial species to prevent toxicity induced by platinum-based chemotherapeutics. Oral treatment of cancer patients with L. acidophilus and Bifidobacterium bifidum prevented intestinal toxicity caused by radiotherapy and cisplatin (Roy and Trinchieri 2017). Experimental results suggest that L. acidophilus stimulates the antitumor activity of cisplatin, meanwhile preventing the toxicity of the drug (Gui et al. 2015; Roy and Trinchieri 2017). Disruption of NOX proteins by acetovanillone prevents cisplatin-derived nephrotoxicity in mice by inhibition of ROS generation in drug-affected proximal tubular cells and consequent ROS generation by myeloid cells (Wang et al. 2015). Therefore, it indicates that the gut commensal microbiota may regulate anticancer effect and toxicity of platinum-derived chemotherapeutic agents by modulating ROS generation in tumors (Wang et al. 2015).
Microbiota and radiotherapy
Ionizing radiation therapy (RTX) induces genotoxicity in cancer cells and may cure certain localized cancers. The classic mechanism of RTX presumed that nucleus was targeted by RTX and DNA damage was caused by energy deposition or generation of ROS via dissociation of water molecules by radiation. However, RTX also affects non-targeted nearby cells and leads to bystander effect, genomic instability and immune-reactivity (Mavragani et al. 2016). These effects are mediated by interruption of gap-junction proteins, release of extracellular mediators such as ROS, cytokines and exosomes (Al-Mayah et al. 2015; Ermolaeva et al. 2013; Nikitaki et al. 2016; Pateras et al. 2015). Therefore, RTX induces release of damage associated molecular pattern (DAMP) signals. Regulation of the response to RTX by microbiota is still controversial. Local irradiation may cause immunogenic death in cancer cells and stimulate systemic immune responses (Kroemer et al. 2013). However, radiation promotes immunostimulating and immunosuppressive responses but it may not be sufficient to initiate an anticancer immune response (Kroemer et al. 2013). RTX induces anticancer responses in non-targeted areas of radiation—referred to as abscopal effect—which are stimulated by immune system (Roy and Trinchieri 2017). Gut microbiota has been proved to modulate the immune response stimulated by immunogenic cytotoxicity in chemotherapy and radiotherapy, its role in immunostimulatory activities of RTX can also be suggested.
The level of RTX-induced mucositis in oral cells and enteropathy may hinder anticancer therapy. Toll-like receptor 3 (TLR3) for double stranded RNA (dsRNA) controls irradiation-initiated cytotoxicity in intestine. Tlr3−/− mice are more susceptible to p53-reliant radiation-derived apoptotic cell death (Takemura et al. 2014; Vacchelli et al. 2013). Concurrently, TLR3-reliant cytotoxicity followed by radiation-derived leakage of RNA has no effect on Tlr3−/− mice. Furthermore, TRX produces less toxicity in Tlr3−/− mice than conventionally raised mice, indicating that inhibition of TRL3-mediated signaling cascades may deplete radiation-induced intestinal toxicity (Takemura et al. 2014; Vacchelli et al. 2013). Radiation-mediated DSBs in the DNA result in cytotoxicity and significant cellular damage by activating the DNA sensor which are not present in melanoma 2 (AIM2) inflammasome (Hu et al. 2016). On the contrary, Toll-like receptor 2 (TLR2)-dependent microbes such as probiotic bacterial specie Lactobacillus rhammosus GG prevent the chemotherapy- and radiotherapy-mediated intestinal toxicity by repositioning cyclooxygenase 2 (COX2)-producing cells from villi to intestinal crypts and promoting ROS generation, which stimulate the cytoprotective NRF2 system (Jones et al. 2013, 2015). Some clinical studies suggest that probiotics are beneficial for preventing RTX-mediated enteropathy. Preparations containing Lactobacillus casei, Streptococcus spp., B. bifidum, and L. acidophilus have been found to significantly deplete the pelvic radiation-mediated toxicity (Touchefeu et al. 2014). Intake of Lactobacillus brevis CD2 containing pills during radiotherapy and chemotherapy for the treatment of head and neck cancer patients reduced the occurrence of anticancer therapy-mediated mucositis (Roy and Trinchieri 2017). Current findings also suggest that microbiota composition regulates the response to irradiation-induced cellular damage. However, the potential of microbiota to permit the genotoxic effects of chemotherapy by inducing ROS generation and immune indicates that the microbiota may also affect the bystander effect of RTX. Recently, it has been shown that normal mice treated with protons are more prone to DSBs in the DNA in peripheral blood leukocytes than mice with controlled microbiota (Maier et al. 2014). Revealing the underlying mechanism of effects of RTX to non-targeted cells and their modulation by microbiota will be very useful for increasing therapeutic efficacy and selectivity, preventing toxicity of RTX and controlling the health hazards of accidental contact with radiation.
Conclusion and future prospectus
Directing ROS to target cancer cells is not only a theoretical approach, but also has went to patient’s beds. Efficacy of both ROS generating and ROS depleting therapies is proved in vitro and in vivo clinical trials. Variation in redox levels of normal and cancerous cells may be used to precise selectivity. Nevertheless, a combination of factors including status of oxidative stress, production of enzymatic antioxidants, signaling cascades and transcription factor promoters need to be developed which subsequently can be used as an suggestive for ROS boosting or ROS scavenging therapy targeting only cancerous cells. Tumors exhibit increased oxidative stress that can stimulate tumor metastasis, and in some cases, cell survival and chemotherapeutic resistance. Directing therapeutic agents toward these biochemical characteristics of tumors with ROS-mediating approaches is a promising strategy that can modulate drug selectivity and reduce chemotherapeutic resistance. Two diverse therapeutic approaches postulated based on the role of ROS in tumor metastasis and oxidative damage. One is to elevate ROS scavenging by intake of antioxidants, therefore, disrupting ROS-mediated signaling cascades and inhibiting cancer metastasis. However, intake of many antioxidant agents during clinical studies was associated with increased tumor development (Bjelakovic et al. 2007). The underlying mechanism might involve inhibition of ROS-derived apoptotic cell death and suppression of ROS-mediated cellular damage in developed tumors subsequently promoting tumor survival. Other strategy is to target tumor cells with pro-oxidant agents that either promote ROS production or inhibit the cellular antioxidants. In preclinical studies, ROS-generating drugs have demonstrated to cause cytotoxicity specifically in cancer cells with elevated endogenous ROS production by overcoming the cellular antioxidants. Synergizing the effect of ROS-producing drugs and agents that inhibit cellular antioxidants can stimulate ROS production and cell death in cancers. However, this strategy might also be involved in mutagenesis in normal cells.
Adaption to altered redox balance is fundamental reason that reveals the mechanism by which tumors develop resistance to ROS-generating chemotherapeutic agents and persist to survive. Elevated intracellular antioxidant activities are a typical feature of tumors and are responsible for anticancer chemotherapeutic resistance. To aid the efficacy of conventional anticancer therapies, the use of drugs to disrupt such fundamental mechanisms in synergy with chemotherapy and radiotherapy is a new strategy. Similarly, the unclear but distinctive, redox alternations in cancer stem cells proposes the development of new ROS-mediating approaches to target cancer stem cells. Due to key role of cancer stem cells in cancer development and chemotherapeutic resistance, the possibility of using a ROS-modulating treatment to kill this subpopulation could have remarkable impacts on effectiveness of conventional anticancer therapies.
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Raza, M.H., Siraj, S., Arshad, A. et al. ROS-modulated therapeutic approaches in cancer treatment. J Cancer Res Clin Oncol 143, 1789–1809 (2017). https://doi.org/10.1007/s00432-017-2464-9
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DOI: https://doi.org/10.1007/s00432-017-2464-9